Cocaine addiction is a significant public health problem, and NIDA remains committed to research on efficacy and mechanisms of candidate treatments for cocaine addiction. During the current funding period, we contributed to a growing body of preclinical and clinical research showing that cocaine consumption can be reduced by maintenance on the monoamine releaser d-amphetamine. More specifically, the efficacy of amphetamine maintenance to reduce cocaine consumption has now been demonstrated in rodents, nonhuman primates, human laboratory studies, and placebo-controlled double-blind clinical trials. Taken together, these findings provide strong evidence for efficacy of amphetamine maintenance as an agonist approach to cocaine abuse treatment that is analogous to treatment of opioid addiction with opioid agonists (e.g. methadone, buprenorphine) or of tobacco dependence with nicotine formulations (e.g. nicotine patch). However, the clinical viability of amphetamine maintenance as an anti-cocaine treatment is limited by amphetamine's own high abuse liability, and it remains unknown if the anti-cocaine effects of amphetamine can be mechanistically dissociated from its abuse-related effects. This application proposes to test mechanisms that underlie the anti-cocaine effects of amphetamine maintenance, and results could suggest new strategies to improve efficacy and safety of anti-cocaine treatments. We propose to focus on potential opioid mechanisms of amphetamine effects, because existing literature supports a role for opioid mechanisms in abuse-related amphetamine effects, but the role for opioid mechanisms in anti-cocaine effects of amphetamine is unknown. The opioid receptor family includes , d and ? receptors, as well as the more recently identified nociceptin/orphanin FQ (NOP) receptors. Aims are proposed to test the hypothesis that activation of and d opioid receptors, but not of ? or NOP receptors, is sufficient and necessary for anti-cocaine effects of amphetamine. Studies will feature an innovative cocaine-vs.-food choice procedure developed by this laboratory for use in nonhuman primates, and treatments will be administered chronically to promote translational relevance. The role of , d, ? and NOP receptors in abuse-related reinforcing and discriminative stimulus effects of amphetamine will also be tested for comparison to data on the role of these receptors in amphetamine's anti-cocaine effects. Results will clarify the relative role of opioid receptors in anti-cocaine vs. abue-related effects of amphetamine. This project will also provide new information on behavioral effects of NOP agonists and antagonists. Lastly, regardless of outcome, the project could have clinical relevance. For example, if opioid receptor activation IS sufficient and necessary, then novel opioid agonists could be targeted as stand-alone or adjunctive candidate anti-cocaine treatments. Alternatively, if opioid receptor activation IS NOT necessary for anti-cocaine effects, then opioid antagonists like naltrexone might be useful as adjuncts to reduce amphetamine abuse liability without impairing amphetamine's anti-cocaine effects.